PRDM9, a driver of the genetic map

Abstract

During meiosis, maternal and paternal chromosomes undergo exchanges by homologous recombination. This is essential for fertility and contributes to genome evolution. In many eukaryotes, sites of meiotic recombination, also called hotspots, are regions of accessible chromatin, but in many vertebrates, their location follows a distinct pattern and is specified by PR domain-containing protein 9 (PRDM9). The specification of meiotic recombination hotspots is achieved by the different activities of PRDM9: DNA binding, histone methyltransferase, and interaction with other proteins. Remarkably, PRDM9 activity leads to the erosion of its own binding sites and the rapid evolution of its DNA-binding domain. PRDM9 may also contribute to reproductive isolation, as it is involved in hybrid sterility potentially due to a reduction of its activity in specific heterozygous contexts.

REC114 partner ANKRD31 controls number, timing and location of meiotic DNA breaks

“…Elsewhere in the genome, where PRDM9 is the major arbiter of hotspot positions, ANKRD31 is important but not essential for normal targeting of SPO11 activity. Since our data suggest that PRDM9 itself is able to function more or less normally in Ankrd31 -/mutants, one possibility is that ANKRD31 directly links SPO11 to PRDM9-established marks, a process that remains poorly understood (Imai et al, 2017;Parvanov et al, 2017;Diagouraga et al, 2018;Grey et al, 2018). An alternative possibility is suggested by the interpretation above that the delay in accumulation of DMC1 foci is because there are fewer and less efficient DSB-forming machines.…”

“…Perhaps the most prominent of these is the pseudoautosomal region (PAR), the small segment where the X and Y chromosomes share homology and must recombine to ensure sex chromosome segregation in male meiosis (Rouyer et al, 1986;Soriano et al, 1987). Although the central roles of PRDM9 DNA binding and histone methylation are clear, the downstream factors that connect these hotspot designation events to SPO11 activity remain to be identified (Grey et al, 2018). The mechanisms of PRDM9-independent SPO11 targeting are likewise poorly understood.…”

Dual Histone Methyl Reader ZCWPW1 Facilitates Repair of Meiotic Double Strand Breaks

“…Meiotic recombination hotspots in mice are primarily determined by PRDM9 binding (Baudat et al, 2010;Davies et al, 2016;Grey et al, 2017;Myers et al, 2010;Parvanov et al, 2010). These hotspots are characterized by PRDM9-dependent histone H3 methylation (H3K4me3 and H3K36me3) (Baker et al, 2014;Grey et al, 2011Grey et al, , 2018Hayashi et al, 2005;Smagulova et al, 2011). To determine whether ZCWPW1 binds to these chromatin sites in vivo, we performed Cleavage Under Targets and Release Using Nuclease (CUT&RUN) (Christoph and Siegenthaler, 2016) using custom polyclonal ZCWPW1 antibodies on mouse spermatocytes.…”

Recombination and selection against introgressed DNA

“…Therefore, introgression generates selection on both local and global modifiers to reduce the recombination rate. Local modifiers of recombination include structural rearrangements (Kirkpatrick 2010), alterations to the binding sites of recombination-specifying proteins (Paigen and Petkov 2018;Grey et al 2018), and mutations that affect local chromatin structure in meiotic prophase [e.g., Stack et al (2017)]. On global modification, note that, even though reducing chromosome number is the most effective way to reduce aggregate recombination , introgression is not expected to select for reduced chromosome number, owing to fertility problems generally experienced by chromosome-number heterozygotes and hybrids (White 1978).…”